1. Field of the Invention
The present invention relates generally to the fields of radioimmunobiology and gene therapy. More specifically, the present invention relates to a novel technique of genetic induction of receptors for targeted radiotherapy.
2. Description of the Related Art
The paradigm of radioimmunotherapy (RAIT) has been based upon the premise that a targeting molecule (e.g. an antibody) carrying a radionuclide has the potential of selectively delivering radiation to tumor sites. Considerable clinical experience with this strategy has been accomplished over the past decade, with success limited primarily to malignant lymphomas (1,2). This limited efficacy reflects fundamental problems in achieving adequate tumor localization of radiolabeled antibodies, which may be due either to inadequate intratumoral expression of the target antigen or to biodistribution problems associated with the use of intact antibody as the targeting moiety (3-6). A variety of strategies have thus been developed as alternatives to radiolabeled intact mouse monoclonal antibodies (MAbs) to enhance tumor localization of an injected radiolabeled ligand, including the employment of second generation high affinity antibodies, humanized antibodies, genetically engineered antibody fragments, peptides, and pretargeting of unlabeled antibody followed by radiolabeled haptens.
"Targeted" radiation therapy is an important cancer research strategy. The use of external beam radiation therapy has produced curative treatment programs for several tumor types. However, this technique has practical limitations in regards to limited field of therapy, normal tissue toxicity, and radioresistance mechanisms. Considerable research efforts have been directed at ways to "target" radioactive isotopes to sites of malignant disease. Currently, the use of monoclonal antibodies directed to "tumor-associated" antigens on cancer cells represents one approach to this problem which has had success in various animal model systems (5-9) and is the subject of considerable current phase I and II trials in man (10-14). Such a strategy provides the ability to localize radioactive isotopes to multiple sites of disease with hopefully adequate amounts of radiation to produce an antitumor effect and/or radioimmune imaging for diagnostic purposes. A second emerging strategy is to use radioactively labeled peptides able to bind to receptor positive tumor cells (e.g. octreotide to somatostatin receptors in malignant carcinoid)(15,16). Research efforts which provide better radioactive isotope delivery systems and/or targeting strategies will enhance the ability to apply targeted radiation therapy.
Radiolabeled monoclonal antibodies (single-step radioimmunotherapy) have serious limitations in treating human cancer. Successful application of radiolabeled monoclonal antibodies in a single-step protocol for radioimmunodetection and radioimmunotherapy of tumors has been hindered in man by problems related to the low percentage uptake of injected radioactivity in tumors (0.001 to 0.1% ID/g), the slow penetration of relatively large (160 kD) intact antibodies into tumors and heterogeneous distribution, their long persistence times in normal tissues leading to high background radioactivity and bone marrow suppression, and the development of human anti-mouse antibody (HAMA) responses. To overcome these problems, several groups have considered the use of antibody fragments and single chain antibodies (17-22), regional administration (23-25), the use of various radionuclides (5), the use of more stable (26) or enzymatically cleavable chelating agents (27), the use of cytokines to upregulate tumor-associated antigen expression (28, 29), irradiation of the tumor to increase vascular permeability (14, 30-32), the use of cytokines to protect against bone marrow suppression (33, 34), and the use of autologous bone marrow transplantation (2, 35). Despite these efforts, the results of clinical radioimmunotherapy of solid tumors have been disappointing. In spite of these shortcomings, antitumor efficacy has been demonstrated in clinical trials for therapy of the radiosensitive lymphoma types of tumors.
The prior art is deficient in the lack of effective means of enhancing the therapeutic effects of immuno-directed radiation therapy. The present invention fulfills this longstanding need and desire in the art.